In this project we used the SIV/macaque model of AIDS for the evaluation of potential vaccine strategies for control of human HIV disease. Emphasis was given to the evaluation of an attenuated vaccinia virus (modified vaccinia virus Ankara; MVA) recombinant expressing the SIVsmH4 gag-pol and env (MVA-SIV) which were compared to a similar recombinant constructed on a Wyeth strain vaccinia virus background (Wyeth-SIV). The Wyeth vaccine virus is a standard vaccine strain used previously in many smallpox immunization campaigns. Four rhesus macaques per immunogen were immunized four times over a 46-week period. Whereas, the MVA-SIV boosted immune response following sequential inoculations, the Wyeth-SIV recombinant only boosted at the second immunization and antibody levels declined subsequently. The antibody response was then boosted with psoralen-inactivated SIV administered without adjuvant. Although immunization did not prevent infection following intravenous challenge with uncloned SIVsm, the dynamics of virus replication were significantly different. Three of the MVA-SIV-vaccinees exhibited sustained control of viremia throughout one year following challenge. This pattern of markedly reduced viremia was associated with maintenance of normal lymphocyte subsets and disease-free status, analogous to longterm nonprogressors of HIV-1 infection. In contrast, three of the Wyeth- vaccinia SIV recombinant and three of the naive control group developed AIDS by one year. These data suggest that immunization with MVA-SIV significantly and beneficially modified the subsequent pathogenesis of SIV infection. As part of our interest in passive immunoprophylaxis and passive immunotherapy we generated a combinatorial phage library of the antibody repertoire of a seven-year, healthy survivor of SIV-infection. Initial screening of the phage-Fab library has yielded four distinct Fabs that bind specifically to SIV envelope. One of these Fabs neutralizes the infectivity of SIV in vitro. Passive transfer of IgG purified from the serum of a long-termsurviving macaque to naive monkeys 24 hours after SIV challenge had a definite therapeutic effect that beneficially retarded progression of disease.